This application is the national stage of PCT/AU98/00726, filed Sep. 8, 1998, now WO 99/12940.
The present invention relates to a method for preparing boron derivatives of organic compounds, in particular to boronic acid derivatives of organic compounds.
Boronic acid derivatives of organic compounds are of particular interest, not only as intermediary means for forming covalent carbon-carbon bonds between organic compounds, but as a starting point for further chemical manipulations and transformations or in conferring or increasing biological activity to otherwise biologically inactive compounds.
Whilst these boronic acid derivatives may be obtained by conventional hydrolysis or hydrogenolysis procedures applied to boronic ester compounds, many conventional conditions employed in the preparation of boronic ester compounds are incompatible with compounds bearing sensitive functionalities. Furthermore, there are practical and commercial advantages in reducing the number of chemical manipulations employed in a synthetic procedure and it is therefore desirable to obtain the boronic acid derivatives directly.
It has now surprisingly been found that diboronic acid can be reacted in the presence of a Group 8-11 metal catalyst with an organic compound under mild conditions to provide boronic acid derivatives directly, thereby circumventing the hydrolysis or hydrogenolysis step and allowing for the presence of sensitive functional groups.
Accordingly, the present invention provides the use of diboronic acid in the preparation of organic boronic acid derivatives containing at least one boronic acid residue.
The invention further provides a process for preparing organic boronic acid derivatives comprising reacting an organic compound having a boron reactive site with diboronic acid in the presence of a Group 8-11 metal catalyst.
The use of diboronic acid offers a convenient and advantageous means of introducing a boronic acid residue into an organic compound over conventional reagents. Its stability towards water and oxygen under ambient conditions provides for ease of use when compared with other reactive and sensitive reagents used to make boronic acids via the esters, which require a strictly controlled environment.
In the preparation of organic boronic acids, the use of diboronic acid affords a number of advantages over that of diboronic acid esters. Firstly, diboronic acid itself is readily prepared from tetra(dimethylamino)diboron. Secondly, the need for a hydrolysis or hydrogenolysis step is circumvented as the boronic acid is the primary reaction product. Thirdly, by avoiding a hydrolysis or hydrogenolysis step, the formation of alcoholic by-products in the reaction mixture is eliminated.
Diboronic acid can be dehydrated (T Wartik and E. F. Apple J Am. Chem. Soc. 1955 77 6400; 1958 80 6155).
nB2(OH)4xe2x86x92[(BO)2]n+2nH2O
It has now been found that the dehydrated form of diboronic acid can also be used to prepare boronic acid derivatives. The boron to boron bond of the dehydrated form is stable in refluxing methanol, ethanol, isopropyl alcohol or t-butyl alcohol and is not cleaved by cold water. The dehydrated form is soluble in methanol at room temperature, dissolves rapidly in ethanol or isopropanol on warning, and in t-butyl alcohol at 82xc2x0 C. (A. L. McClosky, R. J. Brotherton and J. L. Boone, J Am Chem. Soc. 1961 83 4750)
As used herein, the term xe2x80x9cdiboronic acid or tetrahydroxydiboronxe2x80x9d refers to (HO)2Bxe2x80x94B(OH)2 or its dehydration product; and the term xe2x80x9cboronic acid residuexe2x80x9d refers to the group xe2x80x94B(OH)2.
The term xe2x80x9corganic boronic acid derivativexe2x80x9d refers to an organic compound having a boronic acid residue at a substitution position.
The term xe2x80x9cboron reactive sitexe2x80x9d as used herein refers to any carbon atom within a molecule capable of reacting with diboronic acid in the presence of a Group 8-11 metal catalyst to provide a boronic acid residue on that carbon atom. Examples of boron reactive sites include carbon atoms having halogen or halogen-like substituents, carbon atoms taking part in carbon to carbon double or triple bonds, and carbon atoms in an allylic position having a substituent leaving group.
It has been found, in particular, that when an organic compound having a halogen or halogen-like substituent is reacted with diboronic acid in the presence of a Group 8-11 metal catalyst and a suitable base, the halogen or halogen-like substituent on the organic compound can be replaced by a boronic acid residue.
Accordingly, in one embodiment of the invention, there is provided a process for preparing organic boronic acid derivatives which comprises reacting an organic compound having a halogen or halogen-like substituent at a substitution position with diboronic acid in the presence of a Group 8-11 metal catalyst and a suitable base such that the halogen or halogen-like substituent is substituted with a boronic acid residue.
As used herein, the term xe2x80x9corganic compound having a halogen or halogen-like substituent at a substitution positionxe2x80x9d refers to any organic compound having a carbon to halogen or carbon to halogen-like substituent bond at a position at which substitution by a boronic acid residue is desired. The organic compound may be aliphatic, olefinic, acetylenic, aromatic, polymeric, dendritic, cyclic or any combination thereof. The compound may further comprise additional heteroatoms such as sulfur, oxygen, nitrogen, phosphorous, boron, silicon, arsenic, selenium, and tellurium.
The terms xe2x80x9caromaticxe2x80x9d and xe2x80x9caromatic compound(s)xe2x80x9d as used herein refer to any compound which includes or consists of one or more aromatic rings. The aromatic rings may be carbocyclic, or heterocyclic, and may be mono or polycyclic ring systems. Examples of suitable rings include but are not limited to benzene, biphenyl, terphenyl, quaterphenyl, naphthalene, tetradyronaphthalene, 1-benzylnaphthalene, anthracene, dihydroanthracene, benzanthracene, dibenzanthracene, phenanthracene, perylene, pyridine, 4-phenylpyridine, 3-phenylpyridine, thiophene, benzothiophene, naphthothiophene, thianthrene, furan, pyrene, isobenzofuram, chromene, xanthene, phenoxathiin, pyrrole, imidazole, pyrazole, pyrazine, pyrimidine, pyridazine, indole, indolizine, isoindole, purine, quinoline, isoquinoline, phthalazine, quinoxaline, quinazoline, quinoline, pteridine, carbazole, carboline, phenanthridine, acridine, phenanthroline, phenazine, isothiazole, isooxazole, phenoxazine and the like, each of which may be optionally substituted. The terms xe2x80x9caromaticxe2x80x9d and xe2x80x9caromatic compound(s)xe2x80x9d include molecules, and macromolecules, such as polymers, copolymers and dendrimers which include or consist of one or more aromatic rings. The term xe2x80x9cpseudoaromaticxe2x80x9d refers to a ring system which is not strictly aromatic, but which is stabilized by means of delocalization of xcfx80 electrons and behaves in a similar manner to aromatic rings. Examples of pseudoaromatic rings include but are not limited to furan, thiophene, pyrrole and the like.
The term xe2x80x9colefinic compoundxe2x80x9d and xe2x80x9colefinic organic compoundxe2x80x9d as used herein refers to any organic compound having at least one carbon to carbon double bond which is not part of an aromatic or pseudo aromatic system. The olefinic compounds may be selected from optionally substituted straight chain, branched or cyclic alkenes; and molecules, monomers and macromolecules such as polymers and dendrimers, which include at least one carbon to carbon double bond. Examples of suitable olefinic compounds include but are not limited to ethylene, propylene, but-1-ene, but-2-ene, pent-1-ene, pent-2-ene, cyclopentene, 1-methylpent-2-ene, hex-1-ene, hex-2-ene, hex-3-ene, cyclohexene, hept-1-ene, hept-2-ene, hept-3-ene, oct-1-ene, oct-2-ene, cyclooctene, non-1-ene, non-4-ene, dec-1-ene, dec-3-ene, buta-1,3-diene, penta-1,4-diene, cyclopenta-1,4-diene, hex-1,4, diene, cyclohexa-1,3-diene, cyclohexa-1,4-diene, cyclohepta-1,3-diene, cyclohepta-1,3,5-triene and cycloocta-1,3,5,7-tetraene, each of which may be optionally substituted. Preferably the straight chain, branched or cyclic alkene contains between 1 and 20 carbon atoms.
The olefinic compounds may be xcex1,xcex2-unsaturated carbonyl compounds, or conjugated dienes. The term xe2x80x9cconjugated dienesxe2x80x9d as used herein refers to any compound capable of acting as a diene in a Diels-Alder reaction. The olefinic compound may also be an organic compound having a leaving group in an allylic position.
The term xe2x80x9cacetylenic compoundxe2x80x9d as used herein refers to any compound having at least one carbon to carbon triple bond. The acetylenic compounds may be selected from optionally substituted straight chain, branched or cyclic alkynes and molecules, monomers and macromolecules such as polymers and dendrimers, which include at least one carbon to carbon triple bond. Examples of suitable acetylene compounds include, but are not limited to acetylene, propyne, but-1-yne, but-2-yne, pent-1-yne, pent-2-yne, hex-1-yne, hex-2-yne, hex-3-yne, cyclohexyne, hep-1-yne, hept-2-yne, hept-3-yne, cycloheptyne, oct-1-yne, oct-2-yne, oct-3-yne, oct-4-yne, cyclooctyne, nonyne, decyne, 1,3,5-trioctyne, 2,4-dihexyne, each of which may be optionally substituted. Preferably the straight chain, branched or cyclic alkyne contains between 1 and 20 carbon atoms.
The term xe2x80x9csubstitution positionxe2x80x9d as used herein refers to a position on an organic compound at which substitution with a boronic acid residue is desired. Each organic compound may have one or more, preferably between 1 and 6, substitution positions. In an aromatic compound it is preferred that the substitution position is directly on the ring and with an olefinic compound it is preferred that the substitution position is at a vinylic position. If the organic compound is a polymer or a dendrimer it may have many substitution positions.
In this specification xe2x80x9coptionally substitutedxe2x80x9d means that a group may or may not be substituted with one or more groups selected from alkyl, alkenyl, alkynyl, aryl, halo, haloalkyl, haloalkenyl, haloalkynyl, haloaryl, hydroxy, alkoxy, alkenyloxy, aryloxy, benzyloxy, haloalkoxy, haloalkenyloxy, haloaryloxy, isocyano, cyano, formyl, carboxyl, nitro, nitroalkyl, nitroalkenyl, nitroalkynyl, nitroaryl, nitroheterocyclyl, amino, alkylamino, dialkylamino, alkenylamino, alkynylamino, arylamino, diarylamino, benzylamino, imino, alkylimine, alkenylimine, alkynylimino, arylimino, benzylimino, dibenzylamino, acyl, alkenylacyl, alkynylacyl, arylacyl, acylamino, diacylamino, acyloxy, alkylsulphonyloxy, arylsulphenyloxy, heterocyclyl, heterocycloxy, heterocyclamino, haloheterocyclyl, alkylsulphenyl, arylsulphenyl, carboalkoxy, carboaryloxy mercapto, alkylthio, benzylthio, acylthio, sulphonamido, sulfanyl, sulfo and phosphorus-containing groups.
In one aspect of this invention, the organic compound must include at least one halogen or halogen-like substituent at a substitution position to enable reaction with the diboronic acid. The terms xe2x80x9chalogen-like substituentxe2x80x9d and xe2x80x9cpseudo-halidexe2x80x9d refer to any substituent which, if present on an organic compound, may react with diboronic acid in the presence of a palladium catalyst and base to give an organic boronic acid derivative. Preferred halogen substituents include I, Br and Cl. The reactivity of chloro substituted aromatic ring compounds can be increased by selection of appropriate ligands on the palladium catalyst. Examples of halogen-like substituents include triflates and mesylates, diazonium salts, phosphates and those described in Palladium Reagents and Catalysts (Innovations in Organic Synthesis by J. Tsuji, John Wiley and Sons, 1995, ISBN 0-471-95483-7).
As used herein, the term xe2x80x9cleaving groupxe2x80x9d refers to a chemical group which is capable of being displaced by a boronic acid residue. Suitable leaving groups are apparent to those skilled in the art and include halogen and halogen-like substituents, as well as ester groups.
The process according to the present invention is especially suitable for the preparation of organic boronic acid derivatives which contain substituents which are reactive with organometallic compounds, such as Grignard reagents or alkyl lithiums, therefore unsuitable for reacting using standard Grignard methodology unless these substituents are first protected. One such class of reactive substituents are the active hydrogen containing substituents. The term xe2x80x9cactive hydrogen containing substituentxe2x80x9d as used herein refers to a substituent which contains a reactive hydrogen atom. Examples of such substituents include but are not limited to hydroxy, amino, imino, acetyleno, carboxy (including carboxylato), carbamoyl, carboximidyl, sulfo, sulfinyl, sulfinimidyl, sulfinohydroximyl, sulfonimidyl, sulfondiimidyl, sulfonohydroximyl, sultamyl, phosphinyl, phosphinimidyl, phosphonyl, dihydroxyphosphanyl, hydroxyphosphanyl, phosphono (including phosphonato), hydrohydroxyphosphoryl, allophanyl, guanidino, hydantoyl, ureido, and ureylene. Of these substituents it is particularly surprising that the reaction can be conducted with hydroxy and amino substituents in view of their high reactivity. Carboxyl, sulfo and the like (i.e. acidic) substituents may require additional base. Other reactive substituents include trimethylsilyl.
In the above definitions, the term xe2x80x9calkylxe2x80x9d, used either alone or in compound words such as xe2x80x9calkenyloxyalkylxe2x80x9d, xe2x80x9calkylthioxe2x80x9d, xe2x80x9calkylaminoxe2x80x9d and xe2x80x9cdialkylaminoxe2x80x9d denotes straight chain, branched or cyclic alkyl, preferably C1-20 alkyl or cycloalkyl. Examples of straight chain and branched alkyl include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, amyl, isoamyl, sec-amyl, 1,2-dimethylpropyl, 1,1-dimethyl-propyl, hexyl, 4-methylpentyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 1,2,2,-trimethylpropyl, 1,1,2-trimethylpropyl, heptyl, 5-methoxyhexyl, 1-methylhexyl, 2,2-dimethylpentyl, 3,3-dimethylpentyl, 4,4-dimethylpentyl, 1,2-dimethylpentyl, 1,3-dimethylpentyl, 1,4-dimethyl-pentyl, 1,2,3,-trimethylbutyl, 1,1,2-trimethylbutyl, 1,1,3-trimethylbutyl, octyl, 6-methylheptyl, 1-methylheptyl, 1,1,3,3-tetramethylbutyl, nonyl, 1-, 2-, 3-, 4-, 5-, 6- or 7-methyl-octyl, 1-, 2-, 3-, 4- or 5-ethylheptyl, 1-, 2-, or 3-propylhexyl, decyl, 1-, 2-, 3-, 4-, 5-, 6-, 7- and 8-methylnonyl, 1-, 2-, 3-, 4-, 5-, or 6-ethyloctyl, 1-, 2-, 3- or 4-propylheptyl, undecyl, 1-, 2-, 3-, 4-, 5-, 6-,7,8- or 9-methyldecyl, 1-, 2-, 3-, 4-, 5-, 6- or 7-ethylnonyl, 1-, 2-, 3-, 4- or 5-prppylocytl, 1-, 2- or 3-butylheptyl, 1-pentylhexyl, dodecyl, 1-, 2-, 3-, 4-, 5-, 6-, 7-, 8-, 9- or 10-methylundecyl, 1-, 2-, 3-, 4-, 5-, 6-, 7- or 8-ethyldecyl, 1-, 2-, 3-, 4-, 5- or 6-propylnonyl, 1-, 2-, 3- or 4-butyloctyl, 1-2-pentylheptyl and the like. Examples of cyclic alkyl include mono- or polycyclic alkyl groups such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl and the like.
The term xe2x80x9calkoxyxe2x80x9d denotes straight chain or branched alkoxy, preferably C1-20 alkoxy. Examples of alkoxy include methoxy, ethoxy, n-propoxy, isopropoxy and the different butoxy isomers.
The term xe2x80x9calkenylxe2x80x9d denotes groups formed from straight chain, branched or cyclic alkenes including ethylenically mono-, di- or poly-unsaturated alkyl or cycloalkyl groups as previously defined, preferably C2-20 alkenyl. Examples of alkenyl include vinyl, allyl, 1-methylvinyl, butenyl, iso-butenyl, 3-methyl-2-butenyl, 1-pentenyl, cyclopentenyl, 1-methyl-cyclopentenyl, 1-hexenyl, 3-hexenyl, cyclohexenyl, 1-heptenyl, 3-heptenyl, 1-octenyl, cyclooctenyl, 1-nonenyl, 2-nonenyl, 3-nonenyl, 1-decenyl, 3-decenyl, 1,3-butadienyl, 1-4, pentadienyl, 1,3-cyclopentadienyl, 1,3-hexadienyl, 1,4-hexadienyl, 1,3-cyclohexadienyl, 1,4-cyclohexadienyl, 1,3-cycloheptadienyl, 1,3,5-cycloheptatrienyl and 1,3,5,7-cyclooctatetraenyl.
The term xe2x80x9calkynylxe2x80x9d denotes groups formed from straight chain, branched or cyclic alkyne including alkyl and cycloalkyl groups as previously defined which contain a triple bond, preferably C2-20 alkynyl. Examples of alkynyl include ethynyl, 2,3-propynyl and 2,3- or 3,4-butynyl.
The term xe2x80x9cacylxe2x80x9deither alone or in compound words such as xe2x80x9cacyloxyxe2x80x9d, xe2x80x9cacylthioxe2x80x9d, xe2x80x9cacylaminoxe2x80x9d or xe2x80x9cdiacylaminoxe2x80x9d denotes carbamoyl, aliphatic acyl group and acyl group containing an aromatic ring which is referred to as aromatic acyl, or a heterocyclic ring which is referred to as heterocyclic acyl, preferably C1-20 acyl. Examples of acyl include carbamoyl; straight chain or branched alkanoyl such as formyl, acetyl, propanoyl, butanoyl, 2-methylpropanoyl, pentanoyl, 2,2-dimethylpropanoyl, hexanoyl, heptanoyl, octanoyl, nonanoyl, decanoyl, undecanoyl, dodecanoyl, tridecanoyl, tetradecanoyl, pentadecanoyl, hexadecanoyl, heptadecanoyl, octadecanoyl, nonadecanoyl and icosanoyl; alkoxycarbonyl such as methoxycarbonyl, ethoxycarbonyl, t-butoxycarbonyl, t-pentyloxycarbonyl and heptyloxycarbonyl; cycloalkylcarbonyl such as cyclopropylcarbonyl, cyclobutylcarbonyl, cyclopentylcarbonyl and cyclohexylcarbonyl; alkylsulfonyl such as methylsulfonyl and ethylsulfonyl; alkoxysulfonyl such as methoxysulfonyl and ethoxysulfonyl; aroyl such as benzoyl, toluoyl and naphthoyl; aralkanoyl such as phenylalkanoyl (e.g. phenylacetyl, phenylpropanoyl, phenylbutanoyl, phenylisobutylyl, phenylpentanoyl and phenylhexanoyl) and naphthylalkanoyl (e.g. naphthylacetyl, naphthylpropanoyl and naphthylbutanoyl]; aralkenoyl such as phenylalkenoyl (e.g. phenylpropenoyl, phenylbutenoyl, phenylmethacryloyl, phenylpentenoyl and phenylhexenoyl and naphthylalkenoyl (e.g. naphthylpropenoyl, naphthylbutenoyl and naphthylpentenoyl); aralkoxycarbonyl such as phenylalkoxycarbonyl (e.g. benzyloxycarbonyl); aryloxycarbonyl such as phenoxycarbonyl and napthyloxyearbonyl; aryloxyalkanoyl such as phenoxyacetyl and phenoxypropionyl; arylcarbamoyl such as phenylcarbamoyl; arylthiocarbamoyl such as phenylthiocarbamoyl; arylglyoxyloyl such as phenylglyoxyloyl and naphthylglyoxyloyl; arylsulfonyl such as phenylsulfonyl and napthylsulfonyl; heterocycliccarbonyl; heterocyclicalkanoyl such as thienylacetyl, thienylpropanoyl, thienylbutanoyl, thienylpentanoyl, thienylhexanoyl, thiazolylacetyl, thiadiazolylacetyl and tetrazolylacetyl; heterocyclicalkenoyl such as heterocyclicpropenoyl, heterocyclicbutenoyl, heterocyclicpentenoyl and heterocyclichexenoyl; and heterocyclicglyoxyloyl such as thiazolylglyoxyloyl and thienylglyoxyloyl.
The terms xe2x80x9cheterocyclicxe2x80x9d, xe2x80x9cheterocyclylxe2x80x9d and xe2x80x9cheterocyclxe2x80x9d as used herein on their own or as part of a group such as xe2x80x9cheterocyclicalkenoylxe2x80x9d, heterocycloxyxe2x80x9d or xe2x80x9chaloheterocyclylxe2x80x9d refer to aromatic, pseudo-aromatic and non-aromatic rings or ring systems which contain one or more heteroatoms selected from N, S, O and P and which may be optionally substituted. Preferably the rings or ring systems have 3 to 20 carbon atoms. The rings or ring systems may be selected from those described above in relation to the definition of xe2x80x9caromatic compound(s)xe2x80x9d.
The term xe2x80x9carylxe2x80x9d as used herein on its own or as part of a group such as xe2x80x9chaloarylxe2x80x9d and xe2x80x9caryloxycarbonylxe2x80x9d refers to aromatic and pseudo-aromatic rings or ring systems composed of carbon atoms, preferably between 3 and 20 carbon atoms. The rings or ring systems may be optionally substituted and may be selected from those described above in relation to the definition of xe2x80x9caromatic compound(s)xe2x80x9d.
It has also been found that in the presence of a Group 8-11 metal catalyst, diboronic acid may add across a carbon to carbon double or triple bond of an olefinic or acetylenic compound such that a boronic acid residue is introduced on each of the carbon atoms of the respective double or triple bond, such that the double bond becomes a single bond and the triple bond becomes a double bond. In the case of two or more conjugated double bonds the boronic acid residues may be introduced on the distal carbon atoms participating in the conjugation resulting in loss of conjugation. In the case of an xcex1,xcex2-unsaturated carbonyl compound, a single boronic acid residue is introduced on the xcex2-carbon and the xcex1,xcex2-unsaturation is lost.
The term xe2x80x9cdistalxe2x80x9d as used herein in relation to carbon atoms participating in conjugation refers to the carbon atoms at each end of the conjugated chain of carbon atoms. For example, the distal carbon atoms in 1,3-butadiene are carbon atoms 1 and 4.
The expression xe2x80x9closs of conjugationxe2x80x9d as used herein refers to the conversion of a double bond of a conjugated system into a single bond. This may result in complete loss of conjugation or partial loss of conjugation. In some cases there may be some rearrangement following loss of conjugation.
Accordingly, in another embodiment of the invention, there is provided a process for preparing organic boronic acid derivatives which comprises reacting an olefinic organic compound having at least one carbon to carbon double bond or an acetylenic compound having at least one carbon to carbon triple bond, with diboronic acid in the presence of a Group 8-11 metal catalyst such that a boronic acid residue is introduced on one or two of the carbon atoms of the respective double or triple bond.
The term xe2x80x9cGroup 8-11 metal catalystxe2x80x9d as used herein refers to a catalyst comprising a metal of Groups 8-11 of the periodic table described in Chemical and Engineering News, 63(5), 27, 1985.
Examples of Group 8-11 metal catalysts include platinum metal, Pt(O) complexes analogous to the palladium complexes described in detail below, or complexes readily reduceable to the Pt(O) state. Other examples include iron, cobalt, nickel, copper, ruthenium, rhodium, palladium, silver, osmium, iridium, platinum, gold and analogous complexes of these metals. Metals and complexes with readily accessible low oxidative states are particularly suitable. Preferred catalysts are those that readily under oxidative addition and reductive elimination. One skilled in the art would readily be able to select a suitable catalyst on this basis.
When the Group 8-11 metal catalyst is a palladium catalyst it may be a palladium complex. Examples of suitable palladium catalysts include but are not limited to PdCl2, Pd(OAc)2, PdCl2(dppf)CH2Cl2, Pd(PPh3)4 and related catalysts which are complexes of phosphine ligands, (such as (Ph2P(CH2)nPPh2) where n is 2 to 4, P(o-tolyl)3, P(i-Pr)3, P(cyclohexyl)3, P(o-MeOPh)3, P(p-MeOPh)3, dppp, dppb, TDMPP, TTMPP, TMPP, TMSPP and related water soluble phosphines), related ligands (such as triarylarsine, triarylantimony, triarylbismuth), phosphite ligands (such as P(OEt)3, P(O-p-tolyl)3, P(O-o-tolyl)3 and P(O-iPr)3) and other suitable ligands including those containing P and/or N atoms for coordinating to the palladium atoms, (such as for example pyridine, alkyl and aryl substituted pyridines, 2,2xe2x80x2-bipyridyl, alkyl substituted 2,2xe2x80x2-bipyridyl and bulky secondary or tertiary amines), and other simple palladium salts either in the presence or absence of ligands. The palladium catalysts include palladium and palladium complexes supported or tethered on solid supports, such as palladium on carbon, as well as palladium black, palladium clusters, palladium clusters containing other metals, and palladium in porous glass as described in J. Li, A. W-H. Mau and C. R. Strauss, Chemical Communications, 1997, p1275. The same or different palladium catalysts may be used to catalyse different steps in the process. The palladium catalyst may also be selected from those described in U.S. Pat. No. 5,686,608. In certain reactions there are advantages in using ligands with altered basicity and/or steric bulk.
Preferred catalysts are palladium and platinum catalysts as described above. Where the reacting involves an organic compound having a halogen or halogen-like substituent palladium catalysts are especially preferred. Where the organic compound is olefinic or acetylenic platinum catalysts are especially preferred.
It has also been found that when an organic compound containing a carbon to carbon double bond and a leaving group at an allylic position, is reacted with diboronic acid in the presence of a Group 8-11 metal catalyst, the leaving group can be replaced by a boronic acid residue. Preferably the leaving group is an ester group.
Accordingly, in yet another embodiment, there is provided a process for preparing organic boronic acid derivatives which comprises reacting an olefinic compound having a leaving group at an allylic substitution position with diboronic acid in the presence of a Group 8-11 metal catalyst such that the leaving group is replaced with a boronic acid residue.
This reaction may be performed in the presence of a suitable base.
The process may be performed in any suitable solvent or solvent mixture. Examples of such solvents include amides of the lower aliphatic carboxylic acids and lower aliphatic secondary amines, DMSO, aromatic hydrocarbons, nitromethane, acetonitrile, benzonitrile, ethers, polyethers, cyclic ethers, lower aromatic ethers, lower alcohols, and their esters with the lower aliphatic carboxylic acids, pyridine, alkylpyridines, cyclic and the lower secondary and tertiary amines, and mixtures thereof, including mixtures with other solvents.
In a preferred embodiment of the invention the process is performed in a protic solvent. Examples of suitable protic solvents include water and lower alcohols. Most preferably the solvent is water, ethanol, methanol, isopropanol or mixtures thereof, including mixtures with other solvents.
The temperature at which each step of the process according to the invention is conducted will depend on a number of factors including the desired rate of reaction, solubility and reactivity of the reactants in the selected solvent, boiling point of the solvent, etc. The temperature of the reaction will generally be in the range of xe2x88x92100 to 250xc2x0 C. In a preferred embodiment the process is performed at a temperature between xe2x88x9220 and 80xc2x0, more preferably between 15 and 40xc2x0 C.
The term xe2x80x9csuitable basexe2x80x9d as used herein refers to a basic compound which. when present in the reaction mixture, is capable of catalysing, promoting or assisting reaction between reactants. The base may be suitable for catalysing a single step, or more than one step, depending on the desired outcome of the reaction. For example a base may be chosen which catalyses reaction between the organic compound and the diboronic acid, but which is strong enough to catalyse further reaction of organic diboronic acid derivative with additional organic compound or to other organic compounds. It is also preferable that a base is chosen which is soluble in the solvent to which it is added. Examples of bases which are suitable for catalysing the reaction of the organic compound with the diboronic acid include, carboxylates (for example potassium acetate), fluorides, hydroxides, cyanides and carbonates of Li, Na, K, Rb, Cs, ammonium and the group 2 metals Mg, Ca, and Ba, the alkali metal (Li, Na, K, Rb, Cs) phosphates and the phosphate esters (eg. C6H5OP(O)(ONa)2 and related aryl and alkyl compounds) and their alkoxides and phenoxides, thallium hydroxide, alkylammonium hydroxides and fluorides. Some of these bases may be used in conjunction with a phase transfer reagent, such as for example tetraalkylammonium salts or the crown ethers.
It is possible to use stronger bases, such as K2CO3, for catalysing the reaction of an organic compound having a halogen or halogen-like substituent at a substitution position with the diboronic acid by using lower reaction temperatures, for example xe2x88x9220xc2x0 C. to 25xc2x0 C. When coupled product is required this can be achieved by selection of an appropriate temperature. The appropriate temperature will depend on the particular solvent, base and organic compound utilised. It is also possible to control the reaction conditions to form symmetrical coupled products using a strong base. In some cases it may be necessary to raise the temperature of the reaction medium to allow the coupling reaction to proceed. The use of a single base to perform the substitution stage and the coupling step provides a very convenient route to a large range of coupled products.
The term xe2x80x9cvinylic substitution positionxe2x80x9d as used herein refers to a position on the olefinic compound at which substitution with a boronic acid residue is desired and which is located on a carbon atom which is part of an olefinic carbon to carbon double bond. Each olefinic compound may have more than one double bond and therefore more than 2 vinylic coupling positions.
The term xe2x80x9callylic substitution positionxe2x80x9d as used herein refers to a position on the olefinic compound at which substitution with a boronic acid residue is desired and which is located on a carbon atom which is directly next to a carbon atom which is part of an olefinic carbon to carbon double bond.
The invention also provides a process for preparing an organic boronic acid derivative comprising reacting diboronic acid with an organic compound having a halogen or halogen-like substituent and an active hydrogen containing substituent in the presence of a Group 8-11 metal catalyst and a suitable base, such that the halogen or halogen-like substituent is substituted with a boronic acid residue.
In another aspect of the invention there is provided a process for preparing an organic boronic acid derivative comprising reacting diboronic acid with an organic compound having a halogen or halogen-like substituent in the presence of a Group 8-11 metal catalyst. and a suitable base in a protic solvent, such that the halogen or halogen-like substituent is substituted with a boronic acid residue.
In another aspect of the invention there is provided a process for preparing an organic boronic acid derivative comprising reacting diboronic acid with an olefinic or acetylenic compound having respectively at least one carbon to carbon double bond or at least one carbon to carbon triple bond and an active hydrogen containing substituent, in the presence of a Group 8-11 metal catalyst, such that a boronic acid residue is introduced on one or two of the carbon atoms of the respective double or triple bonds.
In another aspect of the invention there is provided a process for preparing an organic boronic acid derivative comprising reacting diboronic acid with an olefinic or acetylenic compound having respectively at least one carbon to carbon double bond or at least one carbon to carbon triple bond, in the presence of a Group 8-11 metal catalyst in a protic solvent, such that a boronic acid residue is introduced on one or two of the carbon atoms of the respective double or triple bonds.
In yet another aspect, there is provided a process for preparing an organic boronic acid derivative which comprises reacting an olefinic compound having a leaving group at an allylic substitution position with diboronic acid in the presence of a Group 8-11 metal catalyst, in a protic solvent, such that the leaving group is replaced by a boronic acid residue.
In yet another aspect, there is provided a process for preparing an organic boronic acid derivative which comprises reacting an olefinic compound having a leaving group at an allylic substitution position and an active hydrogen containing substituent with diboronic acid in the presence of a Group 8-11 metal catalyst, such that the leaving group is substituted with a boronic acid residue.
The process according to the present invention provides a route to organic boronic acid derivatives which could not be readily obtainable using conventional processes. Some of these organic boron acid derivatives are novel and represent a further aspect of the present invention.
Tables 1 and 2 below show the structures of some novel and known organic boronic acid derivatives obtainable according to the process of the present invention.
Accordingly the present invention provides an organic boronic acid derivative of the formula:
Rxe2x80x94B(OH)2
where R is the residue of an organic compound having a substituent reactive with organometallic compounds.
The organic boronic acid derivatives prepared according to the present invention represent a further aspect of the invention and provide suitable intermediates for the coupling of organic compounds via a carbon-carbon bond, or carbon-heteroatom bonds. The organic boronic acid derivatives may also be converted to the corresponding esters or amides by reaction with appropriate alcohols or amines, especially diols and diamines. Surprisingly, it has been found that the presence of appropriate alcohols in the initial stages of the reaction with diboronic acid may be advantageous to the formation of the desired ester product (for example, less dimer formation). Accordingly, performing the reaction in the presence of an appropriate alcohol can give a xe2x80x9cone potxe2x80x9d route to organic boronic esters. Furthermore, the use of alcohols can be used to improve the solubility of the diboron reagents in some solvent systems. Preferably the appropriate alcohol is a diol. If the solvent chosen for the reaction is an alcohol or amine it is also possible in some cases to adjust the reaction conditions such that the boronic acid esters/amides are generated in situ.
Accordingly, in another aspect, the present invention provides a process for covalently coupling organic compounds which comprises reacting an organic boronic acid derivative prepared as herein before described with an organic compound having a halogen or halogen-like substituent at a coupling position in the presence of a Group 8-11 metal catalyst and a suitable base.
According to another aspect the present invention provides a xe2x80x9cone potxe2x80x9d process for preparing an organic boronic acid ester comprising reacting an organic compound having a boron reactive site with diboronic acid in the presence of a Group 8-11 metal catalyst and an appropriate alcohol under conditions such that the organic boronic acid derivative formed by reaction of diboronic acid with the organic compound, reacts with said appropriate alcohol to form said organic boronic acid ester.
In a further aspect there is provided a xe2x80x9cone-potxe2x80x9d procedure for covalently coupling organic compounds comprising reacting:
(i) an organic compound bearing a halogen or halogen-like substituent; or
(ii) an olefinic organic compound; or
(iii) an acetylenic compound
with diboronic acid as hereinbefore defined to form an organic boronic acid derivative, and reacting the organic boronic acid derivative in situ with an organic compound having a halogen or halogen-like substituent at a coupling position in the presence of a Group 8-11 metal catalyst and a suitable base, to form a direct bond between the coupling position and a carbon atom of the organic boronic acid derivative to which the boronic acid residue is attached. This procedure allows the preparation of both symmetrical and unsymmetrical coupled products.
The term xe2x80x9ccoupling positionxe2x80x9d as used herein refers to a position on an organic compound at which coupling to another organic compound is desired. Each organic compound may have one or more, preferably between 1 and 6, coupling positions.
The process according to the present invention is applicable to chemistry on solid polymer support or resin bead in the same manner as conventional chemistry is used in combinatorial chemistry and in the preparation of chemical libraries. That is, wherein the organic compound is chemically linked to a solid support. Thus a suitable organic compound having a halogen or halogen-like substituent at a coupling position which is chemically linked to a polymer surface may be reacted with an organic boronic acid derivative intermediate in the presence of a palladium catalyst and a suitable base to form a coupled product linked to the surface of the polymer. Excess reagents and by-products may then be washed away from the surface leaving only the reaction product on the surface. The coupled product may then be isolated by appropriate cleavage of the chemical link from the polymer surface. The process is also possible using the alternative strategy of reacting (i) an organic compound having a halogen or halogen-like substituent, or (ii) an olefinic organic compound, or (iii) an acetylenic compound, linked to a polymer surface with diboronic acid as previously described to form an organic boronic acid derivative chemically linked to the polymer surface. This derivative may then be reacted with an organic compound having a halogen or halogen-like substituent at a coupling position in the presence of a palladium catalyst and a suitable base to prepare the coupled product chemically linked to the polymer. Excess reactants and by-products may be removed by suitable washing and the coupled product may be isolated by chemically cleaving the link to the polymer.
In accordance with the present invention it is also possible to directly functionalise the surface of a polymer, e.g. polystyrene, with a halogen or halogen-like substituent and then convert this functionalised surface to a boronic acid residue surface by reaction of the functionalised polymer with diboronic acid in the presence of a palladium catalyst and a suitable base. The boronic acid residue surface may then be reacted with any suitable organic compound having a halogen or halogen-like substituent. If the organic compound contains other functional groups, for example carboxylic ester, they may be used as linking groups to further extend the chemical reactions applied to the polymer surface.
The term xe2x80x9clinking groupxe2x80x9d as used herein refers to any chain of atoms linking one organic group to another. Examples of linking groups include polymer chains, optionally substituted alkylene group and any other suitable divalent group.
It is also possible to prepare polymers by reaction of organic ring compounds having more than one halogen or halogen-like substituent. Such organic compounds may be reacted with diboronic acid in the presence of a palladium catalyst and a suitable base to form an organic boronic acid derivative having more than one boronic acid residue. These derivatives may be reacted with organic boronic acid derivative or organic compounds having more than one halogen or halogen-like substituent to form a polymer. If the organic compound has three or more halogen or halogen-like substituents which react with the diboronic acid then it is possible to prepare dendritic molecules in accordance with the process of the present invention. It is also possible to form polymers of organic boronic acid derivatives prepared from olefinic organic compounds and acetylenic compounds where there is more than one boronic acid residue.
The organic compounds which are coupled may be separate molecules or may be linked together such that the organic boronic acid derivative formed after reaction with the diboronic acid is able to react at a coupling position located elsewhere in the molecule so as to provide for an intramolecular reaction, such as a ring closure reaction. Similarly the process according to the invention allows intramolecular linking to occur between different regions bearing halogen or halogen-like substituents.
The process according to the invention is also useful for the preparation of reactive intermediates which are capable of taking part in further reactions or rearrangements. These reactive intermediates may be the organic boronic acid derivatives or the coupled products. For example, aryl boronic acid derivatives may take part in one or more of the palladium catalysed reactions of aryl boron compounds described by Miyaura and Suzuki in Chem. Rev. 1995, 95 2457-2483.
The process according to the present invention allows the linking of organic compounds in mild conditions and avoids the use of expensive, difficult to remove and/or toxic reagents and solvents. In this regard boron and boron compounds are generally non-toxic. The reactions may also be performed in relatively cheap solvents such as methanol and ethanol and, in view of the improved control over the reaction steps, it is envisaged that it would be possible to perform the reactions on an industrial scale. The process also allows the linking of organic compounds which contain active hydrogen substituents without the need to protect those substituents during the reaction.